Cesamet

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Cesamet

CLINICAL PHARMACOLOGY

Pharmacodynamics

Cesamet™ (nabilone) is an orally active synthetic cannabinoid which, like other cannabinoids, has complex effects on the central nervous system (CNS). It has been suggested that the antiemetic effect of nabilone is caused by interaction with the cannabinoid receptor system, i.e. the CB (1) receptor, which has been discovered in neural tissues.

Nontherapeutic Effects: Cesamet (nabilone capsules) , a synthetic cannabinoid, has
the potential to be abused and to produce psychological dependence. Cesamet (nabilone capsules)
has complex effects on the central nervous system. Its effects on the mental
state (i.e., "inner mental life") are similar to those of cannabis.
Subjects given Cesamet (nabilone capsules) may experience changes in mood (e.g., euphoria, detachment,
depression, anxiety, panic, paranoia), decrements in cognitive performance and
memory, a decreased ability to control drives and impulses, and alterations
in the experience of reality (e.g., distortions in the perception of objects
and the sense of time, hallucinations). These phenomena appear to be more common
when larger doses of Cesamet (nabilone capsules) are administered; however, a full-blown picture
of psychosis (psychotic organic brain syndrome) may occur in patients receiving
doses within the lower portion of the therapeutic range.

Data on the chronic use of Cesamet (nabilone capsules) are not available; experience with cannabis
suggests that chronic use of cannabinoids may be associated with a variety of
untoward effects on motivation, cognition, judgment, as well as other mental
status changes. Whether these phenomena reflect the underlying character of
individuals chronically abusing cannabis or are a result of the use of cannabis
is not known.

The simultaneous use of Cesamet (nabilone capsules) and alcohol or barbiturates may produce additive
depressive effects on central nervous system function. Possible changes in mood
and other adverse behavioral effects may occur in patients receiving Cesamet (nabilone capsules) .
Patients should remain under supervision of a responsible adult while using
Cesamet (nabilone capsules) .

Cesamet (nabilone capsules) has central nervous system activity. It produces relaxation, drowsiness,
and euphoria in the recommended dosage range. Tolerance to these effects develops
rapidly and is readily reversible.

In addition to effects on the mental state, Cesamet (nabilone capsules) has several systemic actions; most prominent are dry mouth and hypotension. Cesamet (nabilone capsules) has been observed to elevate supine and standing heart rates and to cause supine and orthostatic hypotension. In clinical studies, oral administration of 2 mg of Cesamet (nabilone capsules) did produce some decrease in airway resistance in normal controls but had no effect in patients with asthma. No other nontherapeutic effects of clinical significance due to Cesamet (nabilone capsules) have been reported.

Pharmacokinetics

Absorption and Distribution: Cesamet (nabilone) appears to be
completely absorbed from the human gastrointestinal tract when administered
orally. Following oral administration of a 2-mg dose of radiolabeled nabilone,
peak plasma concentrations of approximately 2 ng/mL nabilone and 10 ng equivalents/mL
total radioactivity are achieved within 2.0 hours. The plasma half-life (T1/2)
values for nabilone and total radioactivity of identified and unidentified metabolites
are about 2 and 35 hours, respectively. The initial rapid disappearance of radioactivity
represents uptake and distribution of nabilone into tissue and the slower phase
elimination by metabolism and excretion. The apparent volume of distribution
of nabilone is about 12.5 L/kg.

Nabilone exhibits dose linearity within its therapeutic range. Clinical data
suggests that the intake of food does not significantly affect either the rate
or extend of absorption.

Metabolism: Metabolism of nabilone is extensive and several metabolites
have been identified. Precise information concerning the metabolites that may
accumulate is not available. The relative activities of the metabolites and
the parent drug have not been established. There are at least two metabolic
pathways involved in the biotransformation of nabilone. A minor pathway is initiated
by the stereospecific enzymatic reduction of the 9-keto moiety of nabilone to
produce the isomeric carbinol metabolite. The peak concentrations of nabilone
and its carbinol metabolites are comparable, but their combined exposures in
plasma do not account for more than 20% of that of total radioactivity. Secondly,
a metabolite of nabilone in feces has been identified as a diol formed by reduction
of the 9-keto group plus oxidation at the penultimate carbon of the dimethylheptyl
side chain. In addition, there is evidence of extensive metabolism of Cesamet (nabilone capsules)
by multiple P450 enzyme isoforms. In vitro P450 inhibition studies using
human liver microsomes showed that nabilone did not significantly inhibit CYP1A2,
2A6, 2C19, 2D6, and 3A4 (using midazolam and nifedipine as substrates). Nabilone
had a weak inhibitory effect on CYP 2E1 and 3A4 (using testosterone; IC50
> 50 ÁM) and had a moderate inhibitory effect on CYP2C8 and 2C9 (IC50
> 10 ÁM). However, in clinical use, the very low nabilone plasma concentration
is unlikely to interfere with the P450-mediated degradation of co-administered
drugs. Chronic oral administration of 1 mg t.i.d. for 14 days to 3 subjects
gave no indication there was any significant accumulation of nabilone. Available
evidence suggests that one or more of the metabolites has a terminal elimination
half-life that exceeds that of nabilone. Consequently, in repeated use, the
metabolites may accumulate at concentrations in excess of the parent drug.

Elimination: The route and rate of the elimination of nabilone
and its metabolites are similar to those observed with other cannabinoids, including
delta-9-THC (dronabinol). When nabilone is administered intravenously, the drug
and its metabolites are eliminated mainly in the feces (approximately 67%) and
to a lesser extent in the urine (approximately 22%) within 7 days. Of the 67%
recovered from the feces, 5% corresponded to the parent compound and 16% to
its carbinol metabolite. Following oral administration about 60% of nabilone
and its metabolites were recovered in the feces and about 24% in urine. Therefore,
it appears that the major excretory pathway is the biliary system.

The effects of age, gender, hepatic dysfunction, and renal insufficiency on
the metabolism and elimination of nabilone have not been determined.

Special Populations: The pharmacokinetic profile of Cesamet (nabilone capsules) has
not been investigated in either pediatric (See PRECAUTIONS,
Pediatric Use) or geriatric patients (See PRECAUTIONS,
Geriatric Use).

Clinical Trials

Cesamet (nabilone capsules) was evaluated for its effectiveness and safety in the treatment of
nausea and vomiting induced by cancer chemotherapy in patients receiving a wide
variety of chemotherapy regimens, including low-dose cisplatin (20 mg/m2)
in both placebo-controlled and active controlled (prochlorperazine) trials.

During Cesamet (nabilone capsules) treatment patients reported a higher incidence of adverse effects.
The most frequent were drowsiness, vertigo, dry mouth and euphoria. However,
most of the adverse effects occurring with Cesamet (nabilone capsules) were of mild to moderate
severity (See ADVERSE REACTIONS).

Animal Pharmacology and/or Toxicology

Monkeys treated with Cesamet (nabilone capsules) at doses as high as 2 mg/kg/day for a year experienced no significant adverse events. This result contrasts with the findings in a planned 1-year dog study that was prematurely terminated because of deaths associated with convulsions in dogs receiving as little as 0.5 mg/kg/day. The earliest deaths, however, occurred at 56 days in dogs receiving 2 mg/kg/day. The unusual vulnerability of the dog to Cesamet (nabilone capsules) is not understood; it is hypothesized, however, that the explanation lies in the fact that the dog differs markedly from other species in its metabolism of Cesamet (nabilone capsules) .

Last reviewed on RxList: 2/26/2009
This monograph has been modified to include the generic and brand name in many instances.